Recent findings suggest that delta-opioid receptor agonists may play an active role in the suppression of HIV-1 expression in T cells. Conversely delta-receptor antagonists tend to exhibit immunosuppressive properties, and therefore may be useful in transplant therapy. Moreover, animal studies have revealed that delta-receptor antagonists may also be useful in the treatment of alcohol and cocaine abuse. SNC80, a high affinity and very selective delta receptor agonist, was previously synthesized in this Laboratory. We have continued our exploration of the molecular structure-biological activity relationships (SAR) of this molecule, and found that delta binding activity and selectivity showed little change when the aromatic 3- methoxy group in SNC80 was removed or replaced by several other substituents, whereas the N,N-diethylbenzamide group, on the second aromatic ring, is important for interaction with the delta receptor. Extensive modification of the piperazine nucleus led us to synthesize a new series of N,N-diethyl(alpha-piperazinylbenzyl)benzamides, N,N- diethyl(alpha-piperidinyl or piperidinylidenebenzyl) benzamides, and related derivatives. Several of the new compounds had high delta receptor affinity, with Ki values in the low nanomolar range, and they showed negligible affinity for the other opioid receptors (mu and kappa), indicating excellent receptor subtype selectivity. The two nitrogen atoms on the piperazine nucleus showed different SAR in the interaction of this series of compounds at the delta receptor. Nitrogen N4 appears to be an important structural element and is apparently essential for electrostatic interaction, while N1 seems to be unnecessary for recognition at the delta opioid receptor. These data are essential for eventual recognition of the 3-dimensional pattern needed for interaction with opioid receptors. - delta opioid receptor agonists and antagonists, SNC80, structure-activity relationships, SAR, alcohol and cocaine abuse treatment